Abstract
Synthetic and natural ionophores have been developed to catalyze ion transport and have been shown to exhibit a variety of biological effects. We synthesized 24 aza- and diaza-crown ethers containing adamantyl, adamantylalkyl, aminomethylbenzoyl, and ε-aminocaproyl substituents and analyzed their biological effects in vitro. Ten of the compounds (8, 10–17, and 21) increased intracellular calcium ([Ca2+]i) in human neutrophils, with the most potent being compound 15 (N,N’-bis[2-(1-adamantyl)acetyl]-4,10-diaza-15-crown-5), suggesting that these compounds could alter normal neutrophil [Ca2+]i flux. Indeed, a number of these compounds (i.e., 8, 10–17, and 21) inhibited [Ca2+]i flux in human neutrophils activated by N-formyl peptide (fMLF). Some of these compounds also inhibited chemotactic peptide-induced [Ca2+]i flux in HL60 cells transfected with N-formyl peptide receptor 1 or 2 (FPR1 or FPR2). In addition, several of the active compounds inhibited neutrophil reactive oxygen species production induced by phorbol 12-myristate 13-acetate (PMA) and neutrophil chemotaxis toward fMLF, as both of these processes are highly dependent on regulated [Ca2+]i flux. Quantum chemical calculations were performed on five structure-related diaza-crown ethers and their complexes with Ca2+, Na+, and K+ to obtain a set of molecular electronic properties and to correlate these properties with biological activity. According to density-functional theory (DFT) modeling, Ca2+ ions were more effectively bound by these compounds versus Na+ and K+. The DFT-optimized structures of the ligand-Ca2+ complexes and quantitative structure-activity relationship (QSAR) analysis showed that the carbonyl oxygen atoms of the N,N’-diacylated diaza-crown ethers participated in cation binding and could play an important role in Ca2+ transfer. Thus, our modeling experiments provide a molecular basis to explain at least part of the ionophore mechanism of biological action of aza-crown ethers.
Highlights
Crown ethers are macrocyclic polyethers containing three to twenty oxygen atoms separated by two or more carbon atoms, which can be either substituted or unsubstituted
Adamantylamides 1–4 were synthesized by acylation of the corresponding amines with adamantanet-carbonyl chloride in anhydrous chloroform in the presence of trimethylamine (Et3N) (Scheme 1)
We report the synthesis and analysis of twenty-four aza- and diaza-crown ethers with adamantyl, adamantylalkyl, 4-(aminomethyl)benzoyl, and ε-aminocaproyl substituents
Summary
Crown ethers are macrocyclic polyethers containing three to twenty oxygen atoms separated by two or more carbon atoms, which can be either substituted or unsubstituted. Crown ethers possess a hydrophobic ring surrounding a hydrophilic cavity, which enables them to form stable complexes with metal ions, and at the same time to be incorporated in the lipid fraction of the cell membrane. They exhibit ionophore properties by facilitating ion transport across membranes down their electrochemical gradients [1]. A variety of tailored crown ethers have been successfully used as molecular transporters that span the lipid bilayer (e.g., [7]) These macrocycles are exceptionally versatile and can selectively bind to a range of metal ions and a variety of neutral and ionic organic species [8,9]
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